The battle against obesity has been going on for centuries, with little success. The essence of weight reduction is keeping calorie consumption greater than calorie intake. There have been a great number of methods employed to achieve this goal. The most commonly employed method is by taking a very low calorie diet. However, dieters practicing this method almost invariably run into two problems which will eventually fail their effort. Firstly, dieters will feel very hungry and only those who have very strong will power can stick to their semi-starvation dietary regimen. Others may seek the help of various anorectics. However, the efficacy of these anorectics is limited and their central stimulant effect is also worrying. Their use, if indicated at all, is as an adjunct to dietary control in short term management in moderate to severe obesity and requires close medical supervision. The second and even more tricky situation faced by dieters is the feeling of weakness through lack of calories, and hence lack of energy. In biochemical terms, the dieter are faced with the complications arising from starvation.
During starvation, the body has to derive energy from the stored energy, which includes glycogen and fat. In the first instance, the readily available glycogen store in the body is called upon to supply the energy to maintain life's vital processes. But the glycogen store in the body is very limited, equivalent to about 750 calories' worth of energy. Once it is used up, the fat storage of the body will then be mobilized to supply the energy necessary to sustain life. A portion of the body protein will also be broken down, though the tissues of the body are not treated uniformly, the proteins in the brain and the heart are spared more than the proteins in the muscles, liver and spleen. However, in starvation, by and large, the greatest proportion of energy is supplied by the stored neutral fat in the adipose tissue. This is in contrast to the complex fat, which, forming part of the cell structure, is spared until very late. The use of body fat as the main source of energy brings about the formation of ketone bodies, leading to ketosis. This is a serious condition and has important consequences. The name ketone bodies is applied to three substances (acetoacetic acid, B-hydroxybutyric acid and acetone) which form a metabolically-related group. The ketone bodies are mainly produced in the liver.
The normal blood ketone bodies level in a non-fasting person is small (0.5-2 mg per 100 ml). A short-term fast of two or three days, however, may increase this level by as much as fifty-fold. The amount of ketone bodies in the blood at any time depends upon the balance between ketone bodies formation by the liver (hepatic tissue) and the ketone bodies dissimilation by the extra-hepatic tissue. Little is known about the factors that determine ketone bodies dissimilation. However, there is a maximum amount of fat which the tissues can use (mostly as acetoacetic acid), and this amount has been estimated to be around 2.5 gm of fat per kg body weight per day, or equivalent to 175 gm of fat daily in a 70 kg man. The rate of ketogenesis (the generation of ketone bodies) in the liver varies greatly according to circumstances. If ketogenesis proceeds at a high rate, as in starvation, and exceeds the rate of dissimilation in the extra-hepatic tissues, ketone bodies will begin to accumulate in the blood, and be excreted in the urine. In extreme cases of ketosis, urinary ketone bodies output may reach 100-120 gm per day. Obviously, if the ketone bodies can be broken down and metabolized, a biochemical cure of obesity may be possible. An understanding of the formation of ketone bodies at this point would be helpful. When required, the neutral fat is hydrolyzed, releasing glycerol and long-chain fatty acids, the majority containing 16 or 18 carbon atoms. The next stage is the breakdown, mainly in the liver, of these long carbon chains into fragments containing two carbon atoms each. This breakdown process actually involves the conversion of the fatty acid into its high-energy Co A (Coenzyme A) derivative by reaction of the acid with ATP (Adenosine triphosphate) and Co A. This will produce a Co A ester. This Co A ester eventually will react with another Co A, splitting off a acetyl-Co A (a two carbon fragment), leaving the original long-chain fatty acid with two carbon atoms less, but still as a Co A ester. The whole process can be repeated, splitting off a two carbon fragment each time. Thus a 16 C long-chain fatty acid will yield 8 separate fragments of acetyl-Co A. The conventional idea of the fate of the acetyl-Co A in starvation is supposed to be either of the following:
(a) The acetyl-Co A formed can be completely dissimilated via the citric acid cycle if sufficient oxaloacetic acid is available from elsewhere. Coenzyme A is thus freed for further fatty acid cleavage.
(b) Instead of being oxidized, pairs of acetyl-Co A units can react together to form the four carbon ketone body acetoacetic acid. Initially, this condensation produces free Co A and acetoacetyl-Co A, but the latter is rapidly converted to free acetoacetic acid. The acetoacetic acid is distributed to the tissues, and is there oxidized to carbon dioxide and water, liberating energy in the process. The proportion of acetyl-Co A forming acetoacetic acid rather than being immediately oxidized to carbon dioxide is determined by the availability of oxaloacetic acid from some source, e.g., from pyruvic acid or from aspartic acid.
If the rate of carbohydrate dissimilation is depressed (as in starvation), then the availability of oxaloacetic acid is depressed, and the proportion of acetoacetic acid formed will rise. The exact mechanism whereby the acetoacetic acid is metabolized is not known, but one point is quite certain, the body only has a limited means to metabolize the ketone bodies. If the rate of production of the ketone bodies is increased, they will begin to accumulate in the blood and the condition is known as ketosis. A severe degree of ketosis can make an individual feel very sick, weak, and nauseated. The kidneys will try to get rid of the excess ketones via the urine. however, if the function of the kidneys is stretched beyond its limits, the acidic ketones can build up to dangerous, even toxic, levels in the blood. The high acidity can cause the brain to malfunction, leading to loss of consciousness, or even death.
In view of the foregoing, it is apparent that if there is an agent that will burn off all, or most of the acetoacetic acid produced during starvation, the whole problem of weight reduction through a biochemical means would be achieved. This is the primary aim of modern research on obesity, to achieve weight reduction through a biochemical agent. The problem of ketosis, with its sequelae, would be avoided. At the same time, burning off of the acetoacetic acid would mean a lot of energy release, and the problem of hunger and weakness would be solved simultaneously. Hunger sensation is a topic that is poorly understood, but it is known that if the body is well supplied with energy, the sensation is suppressed. It has been mentioned in the foregoing that the body can handle only a small proportion of the acetoacetic acid produced during starvation, but the metabolism of this small proportion of acetoacetic acid is not well understood. It is generally assumed that the acetoacetic acid is first broken down into two Acetyl-Co A by free Co A, these are then oxidized by the enzymes of the citric acid cycle present in the tissue concerned. But there is still a question as to why the majority of the acetoacetic acid molecules are not broken down and metabolized. The very fact that the pairing of the acetyl-Co A units to form acetoacetyl-Co A, liberating a free Co A in the process, and the rapid conversion of acetoacetyl-Co A into acetoacetic acid, liberating yet another Co A molecule, may mean that the body is really deficient in Co A, and that this is an effort to conserve Co A molecules so that long-chain fatty acid can be fragmented. This deficiency in Co A can be a result of deficiency in pantothenic acid, because the other components of Co A are never in short supply. Pantothenic acid, one of the B group of vitamins, is a component of Co A. Pantothenic acid is commercially available from Legere Pharmaceuticals as Dexol TD tablets. According to MARTINDALE, the Extra Pharmacopoeia, 29th edition (1989), pantothenic acid is widely distributed in foods. Meat, legumes, and whole grain cereals are particularly rich sources; other good sources include eggs, milk, vegetables, and fruits. Recommended daily intakes of pantothenic acid have not been set in the U.K. or in the U.S., but human requirements are adequately met by a daily intake of about 4 to 10 mg.
According to Goodman and Gilman's The Pharmacological Basis of Therapeutics, 7th edition (1985), pantothenic acid is a required nutrient, but the magnitude of need is not precisely known. Accordingly, the Committee on Dietary Allowances provides provisional amounts in the form of ranges of intakes (in different age groups). For adults, the provisional allowance is 4 to 7 mg per day. Intakes for other groups are proportional to calorie consumption. Thus, infants will require 2-3 mg per day, and children and adolescents, 3-7 mg per day. in view of the wide-spread distribution of pantothenic acid in foods, dietary deficiency is very unlikely.
If an adequate amount of pantothenic acid is present, providing enough Co A, the metabolism of acetoacetic acid can go on breaking up into two molecules of acetyl-Co A, and henceforth going into the citric acid cycle, to be completely metabolized into carbon dioxide and water, with liberation of energy. Or the adequate supply of Co A may render the pairing of acetyl-Co A and the conversion of acetoacetyl-Co A into acetoacetic acid and Co A unnecessary, so that ketone bodies will not be formed at all. By taking in pantothenic acid, a dieter can take in a low calorie diet containing all the essential nutrients. The extra calories required by the body can be supplied from fat in the fat depot. As long as there is excess fat in the body, it can be burned off in this manner. This method will make weight reduction healthy and effective, but with almost no hunger and weakness. It should be noted that with this method, the body exercise that is stressed so much in conventional weight reduction is not required, though extra exercise will help to burn off the body fat faster, making the process of weight reduction even more effective.
The following is a brief account of Pantothenic Acid: